This invention relates to water soluble prodrugs of rapamycin and in particular to certain derivatives of rapamycin such as, for example, the glycinate prodrugs of rapamycin, the propionate prodrugs of rapamycin and the pyrrolidino butyrate prodrugs of rapamycin.
Rapamycin is a known compound described and claimed in U.S. Pat. Nos. 3,929,992, issued Dec. 30, 1975, and 3,993,749 issued Nov. 23, 1976. Morever, certain of its acyl derivatives are disclosed and claimed in U.S. Pat. No. 4,316,885, issued Feb. 23, 1982.
Rapamycin has been disclosed and claimed as useful in the treatment of tumors in Belgian Pat. No. 877,700. Rapamycin is, however, only very slightly soluble in water, i.e. 20 micrograms per milliliter, and special injectable formulations have been developed for administration to patients, such as those described and claimed in European Pat. No. EP 41,795. These formulations are not altogether satisfactory for a number of reasons including toxicity of the carrier. Accordingly, there is a need in the art for a rapamycin derivative or prodrug which is relatively soluble in water so as to form a safe injectable solution and which is as effective as rapamycin in the treatment of tumors.